Chronic arsenic exposure from drinking water is a serious public health issue in the U.S. and worldwide, as nearly 200 million people worldwide are chronically exposed to this class I human carcinogen. Arsenic increases risk for a wide array of human diseases, including cancers of the skin, bladder, and kidney;however, the mechanisms of arsenic toxicity are unclear. We hypothesize that telomeres may play a critical role in cancer-related arsenic toxicity. Telomeres are central to the regulation of genome stability, and arsenic has detrimental effects on telomeres and telomerase, the primary telomere maintenance enzyme, in a wide variety of experimental settings. In this study, we propose to characterize the relationships among arsenic exposure, various telomere-related traits, and arsenic-related outcomes in a highly feasible and efficient manner, using existing data from a longitudinal cohort study of As exposure in Bangladesh (n=27,000) with ~6-8 years of follow-up data. The proposed study uses a case-cohort design, in which we sample individuals from the cohort study to create three case groups (1,000 incident skin lesion cases, 200 incident non-melanoma skin cancer (MNSC), and 400 deaths) and a single control group (a random sample of 1000 cohort members). Using prospective blood samples, we will measure telomere length, serum markers of telomere dysfunction, and telomerase expression (for a subset with available RNA). Using baseline arsenic exposure data measured in drinking water, urine, and blood, we will assess the effect of arsenic on the measured telomere-related traits among controls and each case group. We will also assess the association between baseline telomere-related traits and our three outcomes of interest. In a second component of this work, we will measure telomere length and telomerase expression in MNSC tissue and adjacent normal tissue obtained from skin biopsies carried out for MNSC cases in this cohort. Telomere-related traits will be compared between normal and cancerous skin and among cancer subtypes, and the association between arsenic exposure and telomere- related traits in skin will be assessed. Finally, we will use existing genome-wide data on germline genetic variants to identify genetic determinants of our telomere-related traits. Several secondary aims will also be addressed. We will (1) determine if telomere-related traits mediate the effect of arsenic on health outcomes, (2) determine if arsenic effects telomere attrition rate, and (3) test telomere-related traits for association with blood levels of antioxidants. This project is a critical step towards understanding the mechanisms of arsenic toxicity in humans. The utility of all telomere-related measures derived from this work will increase as additional follow-up data accumulates in this ongoing cohort study, allowing further study of cancer, cardiovascular disease, and other arsenic-related chronic diseases PUBLIC HEALTH RELEVANCE Exposure to arsenic through drinking water is known to increase risk for mortality and various chronic diseases, including several forms of cancer, but the mechanism or arsenic toxicity is unknown. Using data on a large group of individuals who have been exposed to arsenic through drinking water in Bangladesh, we plan to examine the effects of arsenic on telomeres, which are critical structures on the ends of human chromosomes that protect against damage that can lead to cancer. We also plan to determine if characteristics of telomeres have effects on health outcomes such as mortality, skin lesions, and skin cancer.